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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
The primary transcript produced by RNA polymerase II undergoes post-transcriptional processing to become mRNA that can be translated into protein. Most human genes consist of multiple exons, which is the part of the gene that encodes the protein interspersed by introns or intervening sequences. Introns are removed by spliceosomes and, depending on which exons are retained, different splice variants of the gene can be created. A well-known example relevant to exercise physiology is the alternative splicing of the IGF-I gene to create mechano-growth factor (MGF, also referred to as IGF-IEc in humans or IGF-IEb in rodents), which was discovered by Geoffrey Goldspink’s group in the late 1990s (62). The activity of spliceosomes is in part regulated by proteins that recognise and mark different splice sites, but as yet it is unclear as to how exercise regulates alternative splicing.
Cellular and Immunobiology
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Masood Moghul, Sarah McClelland, Prabhakar Rajan
Pre-mRNA is matured to form mRNA.5' capping protects degradation by RNase by adding a methylated guanine cap.Polyadenylation stabilises RNA by adding a poly(A) tail to the 3' end.Splicing is where non-coding introns are removed by spliceosome excision. Coding exons are joined together by ligation.
Non-VLPs
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Alcid and Jurica (2008) constructed a special labeling protein, termed Beta-PP7, by fusion of the β-subunit of E. coli DNA polymerase III to the PP7 coat, which recognized the corresponding 24-nucleotide RNA hairpin target. This fusion was used to label spliceosomes assembled on a pre-mRNA that contained the target sequence in the exons. The label was clearly visible in electron microscopy images of the spliceosome, and subsequent image processing with averaging showed that the exons sat close to each other in the complex (Alcid and Jurica 2008).
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
The spliceosome (SPL), one of the most complex molecular machineries of eukaryotic cells, is composed of approximately 150 proteins and 5 small nuclear (sn)RNAs (U1, U2, U4, U5, and U6 snRNPs), which assemble into 5 small ribonucleoprotein complexes (snRNPs) through entangled protein/RNA networks. At each splicing cycle, the SPL assembles on nascent pre-mRNA transcripts and catalyzes pre-mRNA splicing in a tightly orchestrated process. During the splicing cycle, the SPL visits several intermediate states (E, A, B, Bact, B*, C, C*, P, and ILS, Figure 1(a)) and undergoes massive conformational and compositional changes driven by specific helicases [4]. The paramount importance of splicing is highlighted by the fact that up to one-third of all disease-causing mutations are associated with splicing defects [5].
Splicing deregulation, microRNA and notch aberrations: fighting the three-headed dog to overcome drug resistance in malignant mesothelioma
Published in Expert Review of Clinical Pharmacology, 2022
Dario P. Anobile, Giulia Montenovo, Camilla Pecoraro, Marika Franczak, Widad Ait Iddouch, Godefridus J Peters, Chiara Riganti, Elisa Giovannetti
Pre-mRNA is only functional for protein synthesis after the removal of introns and when the exons are spliced together. The spliceosome is responsible for splicing out introns from pre-transcribed mRNA (Figure 4). The splicing process is essential for the regulation of gene expression in eukaryotes. Mutations or differentially expressed splicing factors (SF) that form the spliceosome are common in cancer and lead to splicing deregulation such as exon skipping, intron retention and alternative splicing sites. This results in the production of aberrant mRNA splicing patterns. which affect biological processes related to chemoresistance, including decreased transport of the anticancer drugs into the intracellular space, impaired conversion to an active metabolite, altered regulation of target gene transcription and apoptosis [118]. Moreover, alternative splicing leads the formation of cancer-specific splicing isoforms, which produce transcriptome changes relevant for many processes underlying tumor biology [119]. For instance, an incorrect splicing of BAP1 mRNA can impair correct protein formation, as described by Morrison and colleagues, who identified a novel homozygous substitution mutation, BAP1 c.2054 A&T (p.Glu685Val). This causes aberrant splicing and premature truncation of the BAP1 protein, resulting in genomic instability [18].
Nucleic acid therapeutics: a focus on the development of aptamers
Published in Expert Opinion on Drug Discovery, 2021
Swati Jain, Jaskirat Kaur, Shivcharan Prasad, Ipsita Roy
Small nucleic acids may also act via trans-splicing at the post-transcriptional level. Trans-splicing is catalyzed by the cellular spliceosome machinery which substitutes intrinsic unwanted sequences in the pre-mRNA with the correct sequence containing built-in donor and acceptor splice sites and a hybridization domain for targeted action. This results in a mutation-free, chimeric functional mRNA transcript [15–17]. Spliceosome-mediated RNA trans-splicing (SMaRT) was used to correct LMNA (lamin A)-related congenital muscular dystrophy in mice [16]. Pre-trans-spliced molecules (PTMs) containing the wild-type lamin A coding sequence, flanked by splicing sites and a hybridization domain were used to target mutant intron 5 of lamin A pre-mRNA by an adenoviral vector. Although the trans-splicing efficiency was quite low, it was sufficient to improve phenotype in homozygous LmnaΔK32 mice [16], showing the promise of the approach.